Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Children's Research Institute, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
Dev Dyn. 2010 Jul;239(7):2118-27. doi: 10.1002/dvdy.22346.
Myxoid degeneration of the cardiac valves is a common feature in a heterogeneous group of disorders that includes Marfan syndrome and isolated valvular diseases. Mitral valve prolapse is the most common outcome of these and remains one of the most common indications for valvular surgery. While the etiology of the disease is unknown, recent genetic studies have demonstrated that an X-linked form of familial cardiac valvular dystrophy can be attributed to mutations in the Filamin-A gene. Since these inheritable mutations are present from conception, we hypothesize that filamin-A mutations present at the time of valve morphogenesis lead to dysfunction that progresses postnatally to clinically relevant disease. Therefore, by carefully evaluating genetic factors (such as filamin-A) that play a substantial role in MVP, we can elucidate relevant developmental pathways that contribute to its pathogenesis. In order to understand how developmental expression of a mutant protein can lead to valve disease, the spatio-temporal distribution of filamin-A during cardiac morphogenesis must first be characterized. Although previously thought of as a ubiquitously expressed gene, we demonstrate that filamin-A is robustly expressed in non-myocyte cells throughout cardiac morphogenesis including epicardial and endocardial cells, and mesenchymal cells derived by EMT from these two epithelia, as well as mesenchyme of neural crest origin. In postnatal hearts, expression of filamin-A is significantly decreased in the atrioventricular and outflow tract valve leaflets and their suspensory apparatus. Characterization of the temporal and spatial expression pattern of filamin-A during cardiac morphogenesis is a crucial first step in our understanding of how mutations in filamin-A result in clinically relevant valve disease.
心脏瓣膜黏液样变性是一组异质性疾病的常见特征，包括马凡综合征和孤立性瓣膜病。二尖瓣脱垂是这些疾病中最常见的结果之一，仍然是瓣膜手术最常见的指征之一。虽然病因不明，但最近的遗传研究表明，一种 X 连锁的家族性心脏瓣膜发育不良可归因于细丝蛋白 A 基因的突变。由于这些可遗传的突变从受孕时就存在，我们假设在瓣膜形态发生时存在细丝蛋白 A 突变会导致功能障碍，这种功能障碍在出生后进展为具有临床意义的疾病。因此，通过仔细评估在 MVP 中起重要作用的遗传因素（如细丝蛋白 A），我们可以阐明与其发病机制相关的发育途径。为了了解突变蛋白的发育表达如何导致瓣膜疾病，首先必须描述细丝蛋白 A 在心脏形态发生过程中的时空表达分布。尽管以前被认为是一种广泛表达的基因，但我们证明细丝蛋白 A 在心脏形态发生过程中的非心肌细胞中强烈表达，包括心外膜和心内膜细胞，以及 EMT 从这两种上皮衍生的间质细胞，以及神经嵴来源的间质细胞。在出生后心脏中，细丝蛋白 A 在房室瓣和流出道瓣叶及其悬吊装置中的表达显著降低。在心脏形态发生过程中，细丝蛋白 A 的时空表达模式的特征是我们理解细丝蛋白 A 突变如何导致具有临床意义的瓣膜疾病的关键的第一步。
